DESCRIPTION (provided by candidate): This is a submission of an application for a mentored patient-oriented K-23 award, designed to enhance clinical training and research expertise in the area of major depressive disorder on (MDD) and the role of natural remedies in the development and treatment of depressive disorders. Natural remedies, although used for centuries throughout the world, have become increasingly popular in the US over the past few years. S-adenosyl methionine (SAMe) is one such compound. Although results obtained from double-blind preliminary studies support the hypothesis that this compound may have antidepressant effects, oral SAMe has not yet been studied as a potential augmenting agent for contemporary, first-line antidepressants, such as the Selective Serotonin Reuptake Inhibitors (SSRIs). As many as 29% to 46% of depressed patients show only partial or non-response to an adequate course of an antidepressant, with most patients taking an SSRI as an initial treatment. The goal of this project will be to assess the efficacy of oral SAMe compared to placebo as an augmentor of SSRIs in the treatment of major depression refractory to treatment with SSRIs. This application involves enrolling outpatients with MDD, with partial or no response to an SSRI trial of adequate dose and duration. Patients will be treated for 6 weeks in a double-blind fashion with either oral SAMe tosylate, up to 1600mg/day, or placebo for 6 weeks. We hypothesize that there will be a statistically significant difference in the response rates between the two treatment groups at endpoint, with a greater response rate in the group that received SAMe augmentation. The proposed study will be based at the Massachusetts General Hospital in the Depression Clinical and Research Program, under the mentorship of Maurizio Fava, MD, and will include consultation from experts in the area of MDD, alternative medicine, and biostatistics. There will also be a didactic component to the application project, including coursework research design, neuronal biology, biostatistics, and ethics. It is hoped that this project award will provide the critical fund of basic knowledge and practical experience necessary to aid the candidate in becoming an independent investigator in this area.